15-23566108-G-A

Position:

• chr15-23566108-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_005664.4(MKRN3):​c.326G>A​(p.Cys109Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MKRN3 NM_005664.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.54

Genes affected

MKRN3 (HGNC:7114): (makorin ring finger protein 3) The protein encoded by this gene contains a RING (C3HC4) zinc finger motif and several C3H zinc finger motifs. This gene is intronless and imprinted, with expression only from the paternal allele. Disruption of the imprinting at this locus may contribute to Prader-Willi syndrome. An antisense RNA of unknown function has been found overlapping this gene. [provided by RefSeq, Jul 2008]

ENSG00000260978 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 15-23566108-G-A is Pathogenic according to our data. Variant chr15-23566108-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 625144.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-23566108-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MKRN3	NM_005664.4	c.326G>A	p.Cys109Tyr	missense_variant	1/1	ENST00000314520.6	NP_005655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MKRN3	ENST00000314520.6	c.326G>A	p.Cys109Tyr	missense_variant	1/1	6	NM_005664.4	ENSP00000313881.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Precocious puberty, central, 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetics and Personalized Medicine Clinic, Tartu University Hospital

Mar 24, 2019

4 patients with central precocious puberty were members of one big family and had the same heterozygous paternally inherited mutation. As the phenotype is specific, segregates well in family, multiple computational tools support damaging effect, and mutation is absent from gnomAD, we classify it as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Pathogenic	2.9	M
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-9.2	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.053	T
Polyphen		1.0	D
Vest4		0.96
MutPred		0.86		Loss of methylation at K110 (P = 0.0427);
MVP		0.95
MPC		0.51
ClinPred		1.0	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1566764505; hg19: chr15-23811255;